Case Report

Irritability, Poor Feeding and Respiratory Alkalosis

in Newborns: Think about Metabolic Emergencies.
A Brief Summary of Hyperammonemia Management
Stefano Del Re 1, *, Aurélie Empain 2 , Alfredo Vicinanza 3 , Ovidiu Balasel 1 ,
Anne-Britt Johansson 1 , Jean-Philippe Stalens 4 and Corinne De Laet 2
1 Neonatal Intensive Care Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles,
1020 Brussels, Belgium; ovidiu.balasel@huderf.be (O.B.); anne-britt.johansson@huderf.be (A.-B.J.)
2 Department of Nutrition and Metabolism, Hôpital Universitaire des Enfants Reine Fabiola,
Université Libre de Bruxelles, 1020 Brussels, Belgium; aurelie.empain@huderf.be (A.E.);
corinne.delaet@huderf.be (C.D.L.)
3 Pediatric Intensive Care Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles,
1020 Brussels, Belgium; alfredo.vicinanza@huderf.be
4 Neonatal Non-Intensive Care Unit, Centre Hospitalier de Wallonie Picarde (Site Union),
7500 Tournai, Belgium; jean-philippe.stalens@chwapi.be
* Correspondence: stefanodelre@hotmail.com; Tel.: +32-496-616024




Received: 25 June 2020; Accepted: 27 July 2020; Published: 25 October 2020


Abstract: The urea cycle is a series of metabolic reactions that convert ammonia into urea in
order to eliminate it from the body. Urea cycle disorders are characterized by hyperammonemia,
which can cause irreversible damages in central nervous system. We report a series of three
newborns presenting irritability, poor feeding and tachypnea. Their first gas analysis revealed
respiratory alkalosis. Hyperammonemia was confirmed, and three different enzymatic blocks in
the urea cycle were diagnosed. Immediate treatment consisted in the removal of ammonia by
reduction of the catabolic state, dietary adjustments, use of nitrogen scavenging agents and ultimately
hemodiafiltration. Hyperammonemia is a medical emergency whose treatment should not be delayed.
This report aims to highlight the importance of suspecting urea cycle disorders in newborns with
aspecific signs of hyperammonemia and respiratory alkalosis, and to sum up the broad lines of
hyperammonemia management.

Keywords: hyperammonemia; respiratory alkalosis; urea cycle disorder; newborn; continuous

venovenous hemodiafiltration

1. Introduction
The urea cycle is a metabolic pathway involved in nitrogen detoxification and arginine synthesis [1].
It requires six enzymes and two transporters [2]. Any total or partial enzyme deficiency or transport
defect in this pathway leads to a urea cycle disorder (UCD), resulting in acute hyperammonemia except
for the arginase deficiency [3].
Hyperammonemia is neurotoxic and can cause irreversible damages in the central nervous system;
it has to be considered as a medical emergency [4]. The initial symptoms of hyperammonemia are
hyperventilation with irritability evolving to coma [1]. Hyperventilation in UCDs is a common early
finding which causes respiratory alkalosis. That is thought to result from astrocyte swelling responsible
of cerebral edema caused by the accumulation of ammonia, glutamine and other metabolites when
osmoregulation is insufficient [5]. Increasing cerebral edema may result in progressive encephalopathy
with hypoventilation and respiratory arrest.

Pediatr. Rep. 2020, 12, 77–85; doi:10.3390/pediatric12030019 www.mdpi.com/journal/pediatrrep

Pediatr. Rep. 2020, 12 78

Urea cycle disorders have autosomal recessive inheritance pattern except for ornithine
transcarbamylase (OTC) deficiency, which is X-linked [6]. The estimated combined incidence of
these disorders is 1/55,000 live births in the USA and in Europe [7].
The initial presentation can occur at any age; approximately half of all patients are newborns
developing symptoms within the first 12 to 48 h after birth. Different factors as catabolism (acute infection,
fever, surgery, trauma, fasting) or increased protein intake may trigger the hyperammonemic crisis [8].
No specific clinical signs could help distinguish the different types of urea cycle defect, except for
hyperargininemia (or arginase deficiency), whose clinical manifestations may progressively take
hold in affected subjects, such as progressive spastic diplegia (or quadriplegia) as well as ataxia and
developmental delay around the age of two to four years [1].
The diagnosis of UCD can be made either on clinical basis or by neonatal screening in some
countries. Newborn screening allows an early diagnosis and intervention even before symptoms appear.
Screening programs are essentially based on the Wilson and Jungner criteria [9] and target illnesses
with important health issue whose early diagnosis and treatment can lead to a direct improvement in
the patient’s quality of life. However, variations in the criteria for neonatal screening have emerged as
a result of technological progress (molecular biology, mass spectrometry), medical advances and even
public demand. Thus, the list of diseases that can now be detected in the neonatal period is becoming
technically very important and should be constantly updated. Therefore, the number and nature of
the screened diseases vary enormously by country [10]. In Belgium, both the Dutch speaking and the
French speaking communities use the Guthrie test for their neonatal screening programs. The list
of the diseases to screen is decided by each community, according to their own legal criteria. In the
French speaking community, argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL)
deficiencies can be detected but are not routinely requested. Carbamoyl-phosphate synthase 1 (CPS1)
and OTC deficiencies are more difficult to detect because their metabolites are technically difficult to
quantify [10].
We report three cases of newborns with irritability, tachypnea and feeding problems. Their initial
blood gas analysis showed respiratory alkalosis, thus suggesting hyperammonemia. This observation
allowed a rapid diagnostic orientation with adequate therapeutic management.

2. Case Reports
The three reported patients were admitted to neonatal or pediatric intensive care units between
April and October 2017.
Their gestational ages ranged from 36 to 41 weeks. Pregnancy was properly monitored and
uneventful for all of them. Birth weights were normal for gestational age, except for case 3 who was
dysmature (Table 1). No consanguinity was reported among the parents of the three patients. They did
not require any cardiopulmonary resuscitation in delivery room. They were admitted to the neonatal or
pediatric intensive care units between the first and the seventh day of life owing to similar symptoms
as poor feeding, lethargy, irritability and sleepiness. Respiratory distress and hyperventilation were
remarkable as well (Table 1).

Table 1. Personal information, symptoms, diagnostic laboratory data and diagnosis of the cases.

Case 1 Case 2 Case 3

Gestational age (weeks) 41 + 1/7 39 36
Birth weight (grams) 3260 3830 2035
Gender Boy Boy Girl
Admission to intensive care
2 1 7
unit (days of life)
Sleepiness; Hypotonia Sleepiness; Lethargy; Irritability;
Symptoms at admission Irritability and poor feeding
Irritability; Tachypnea Tachypnea
Respiratory alkalosis (pH 7.60; Respiratory alkalosis (pH 7.52; Respiratory alkalosis (pH 7.55;
Initial blood gas
pCO2 22.3 mmHg; HCO3 pCO2 24 mmHg; HCO3 pCO2 26 mmHg; HCO3
analysis (capillary)
21.5 mmol/L) 19.5 mmol/L) 22 mmol/L)
Pediatr. Rep. 2020, 12 79

Table 1. Cont.

Case 1 Case 2 Case 3

Initial ammonia plasma
775 527 845
level (µmol/L)
Low plasma levels of citrulline,
argininosuccinic acid and Low plasma levels of citrulline
High plasma level of citrulline;
Blood amino acids arginine; and arginine;
High plasma level of glutamine
High plasma level of High plasma level of glutamine
glutamine
Urinary orotic acid High Normal High
Ornithine transcarbamylase Carbamoyl-phosphate synthetase Argininosuccinic acid synthetase
Diagnosis
(OTC) deficiency (CPS) deficiency (ASS) deficiency
Mutation in variants c.773 + 49C >
Mutation in c996G > A Missense mutation c.4142C > T
T and c.1168G > A (pGly390Arg)
Genetic analysis (p.Trp332) of the OTC gene in (pLeu1381Ser) in exon 35 of the
of the ASS1 gene in a
a haemizygote state CPS 1 gene in a heterozygous state
heterozygous state
Length of stay in intensive
28 24 8
care unit

Their infectious laboratory workups were negative. The first blood gas analysis revealed respiratory
alkalosis for all of them, which led us to measure ammonemia. Initial plasma ammonia levels were
high between 527 and 788 µmol/L (normal range: 48–110 µmol/L) (Table 1). As metabolic disorders
were suspected, urea cycle intermediates were especially investigated.
The immediate first therapeutic line for all patients consisted in invasive ventilation support
because of neurologic impairment, glucose infusion (10 mg/kg/min) after stopping protein
intake, administration of ammonia scavengers (intravenous sodium benzoate) and arginine.
Protein-free therapy was instituted rapidly to prevent a rebound of plasma ammonia levels. Parenteral
nutrition containing lipids and glucose was assured to optimize caloric intake and to prevent catabolic
state. Proteins and essential amino acids (EAA) were reintroduced after 24 to 48 h. As since enteral
feeding was tolerated (between two and eight days after admission to intensive care units), the patients
received a low-protein diet adapted to plasma ammonia levels and plasma amino acids. Despite first-line
therapy, hyperammonemia persisted in each case and blood gases progressed to acidosis for the two
boys. Therefore, continuous venovenous hemodiafiltration (CVVHDF) was rapidly initiated for all of
them, thus permitting a significant decrease in plasma ammonia levels (Figure 1).
Biochemical investigations including hepatic enzymes, glycemia, lactatemia, plasma amino acids,
urinary orotic acid, urinary ketone bodies and urinary organic acids were performed to find the enzyme
deficiency. Plasma glutamine was increased in all patients. Three different UCDs were identified:
the ornithine transcarbamylase (OTC) deficiency, the carbamoyl-phosphate synthetase (CPS) deficiency
and the argininosuccinic acid synthetase (ASS) deficiency.
Carglumic acid, generally used for the treatment of hyperammonemia in patients with
N-acetylglutamate synthase deficiency [1,11] was started empirically along with the first therapeutic
line. Due to its inefficiency in the management of hyperammonemia in our patients, and after receiving
the results of the first biological tests (12 to nearly 48 h after starting dialysis), which excluded
a deficiency in N-acetylglutamate synthase, this treatment was, therefore, stopped (Figure 1).
Electroencephalography, performed shortly after admission to intensive care units,
was pathological in all of them, showing an epileptic activity or asynchronous slow waves with
clinical signs of encephalopathy. Thus, anticomitial therapy was administered to manage seizures.
Electrophysiological, as well as neurologic signs improved in all patients, thus correlating with the
ammonia plasma level drop. Cranial ultrasounds were non-contributory in all cases. Nevertheless,
one to two weeks after the onset of symptoms, every patient had abnormal cerebral magnetic resonance
showing the presence of ischemic lesions in sparse spots pattern or abnormalities in white matter
without cerebral edema.
Pediatr.
Pediatr. Rep. 2020, 12
Rep. 2020, 12, FOR PEER REVIEW 804

Figure 1. Evolution of ammonemia.

Figure 1. ammonemia.

Genetic analysis
Biochemical confirmed these
investigations threehepatic
including diagnosis. Different
enzymes, methodslactatemia,
glycemia, were usedplasmaincluding the
amino
parallel mass sequencing method (on a panel of 3989 genes associated with
acids, urinary orotic acid, urinary ketone bodies and urinary organic acids were performed to find metabolic diseases).
The mutations
the enzyme found inPlasma
deficiency. the ASS 1, CPS 1 was
glutamine and increased
OTC 1 genes in allconfirm
patients.the threedifferent
Three diagnosis (Table
UCDs 1).
were
These variants, already described, are associated with the observed phenotypes.
identified: the ornithine transcarbamylase (OTC) deficiency, the carbamoyl-phosphate synthetase A genetic analysis
was
(CPS)also requested
deficiency andfrom the parents of our
the argininosuccinic acidpatients:
synthetasecase(ASS)
1’s mother was found to be a carrier of
deficiency.
the mutation;
Carglumic acid, generally used for the treatment of hyperammonemia the
for case 2, both parents are found to be carriers of the mutation; parents of
in patients caseN-
with 3,
unfortunately, were not able to perform genetic analysis.
acetylglutamate synthase deficiency [1,11] was started empirically along with the first therapeutic
line. Their
Due treatment at discharge
to its inefficiency wasmanagement
in the the same: low-protein and high-energy
of hyperammonemia diet,patients,
in our sodium benzoate,
and after
L-citrulline and arginine.
receiving the results of the first biological tests (12 to nearly 48 h after starting dialysis), which
At 14amonths
excluded of age,
deficiency the psychomotor development
in N-acetylglutamate synthase, this fortreatment
case 3 waswas,normal. Her movements
therefore, were
stopped (Figure
fluid
1). and well-coordinated. Case 2 exhibited mild axial hypotonia at the same age; despite this,
his movements were fluid and
Electroencephalography, well-coordinated
performed as well.
shortly after Nevertheless,
admission to intensivehe required
care units,Bobath
was
physiotherapy
pathological insupport. Their
all of them, growth an
showing parameters
epileptic were within
activity normal limits slow
or asynchronous for age. Unlike
waves theclinical
with other
ones,
signs case
of 1encephalopathy.
had more severe Thus,neurologic sequelae with
anticomitial overall
therapy wasdevelopment
administereddelay,toaxial hypotonia
manage and
seizures.
persistent seizures.
Electrophysiological, as well as neurologic signs improved in all patients, thus correlating with the
Because
ammonia of the
plasma poor
level quality
drop. of life,
Cranial the constraints
ultrasounds due to the diet with
were non-contributory in all recurrent metabolic
cases. Nevertheless,
decompensations and hospitalizations, cases 1 and 2 underwent a liver transplant
one to two weeks after the onset of symptoms, every patient had abnormal cerebral magnetic at 10 and 16 months
of age, respectively.
resonance showing the presence of ischemic lesions in sparse spots pattern or abnormalities in white
matter without cerebral edema.
Pediatr. Rep. 2020, 12 81

3. Discussion
This report aims to highlight the importance of non-specific signs and especially respiratory
alkalosis in newborns as a clue of suspicion for urea cycle disorders. Hence, this might lead clinicians
to measure ammonemia in such neonatal cases.
Moreover, urea cycle disorders are not frequently encountered in the routine practice of
pediatricians and neonatologists. Consequently, most physicians have relatively little experience in the
management of hyperammonemia. As hyperammonemic crisis could cause severe neurologic sequelae,
this should be considered as a medical emergency and first-line treatment should not be delayed.
Immediate treatment is important in term of prognosis. Therefore, starting from the description of three
cases, another purpose of this work is to take a look at the acute management of hyperammonemia
in newborns.
Hyperventilation in UCDs is a common early finding which causes respiratory alkalosis. As noted
in two of our cases, respiratory alkalosis can progress to acidosis, mostly if UCDs are diagnosed and
treated late [1,5]. A blood gas analysis is, therefore, useful to guide the diagnosis of this type of
metabolic disorders. Respiratory alkalosis (high serum bicarbonate and high arterial pH) with normal
anion gap and blood glucose in a newborn should prompt immediate plasma ammonia measurement,
as hyperammonemia is initially present in 50% of acute urea cycle disorders [1].
Hyperammonemia is defined as a plasma ammonia level greater than 110 µmol/L for neonates
born at term. However, hyperammonemia is present in UCDs mostly at higher values (>200 µmol/L) [4].
If the ammonia plasma value is between 110 and 200 µmol/L, a control is recommended. For premature
infants, upper limit values of ammonemia may be higher (between 110 and 200 µmol/L). An idiopathic
disorder known as transient hyperammonemia of the newborn (THAN) can occasionally be present
in preterm newborns as well, characterized by a normal blood glutamine level and not always
symptomatic [1]. If plasma ammonia is elevated, further basic laboratory and metabolic investigations
(determination of plasma amino acids, plasma acylcarnitines, urinary organic acids and orotic acid)
might be immediately carried out without delaying specific treatment [1].
The initial symptoms of UCDs are very aspecific in newborns: tachypnea, lethargy, irritability,
poor feeding and sleepiness. The most common misdiagnosis is neonatal sepsis [12]. In Figure 2
we propose a diagnostic algorithm useful for newborns presenting aspecific clinical signs
of hyperammonemia.
Besides UCDs, other causes of hyperammonemia should be considered as well. Hyperammonemia
in neonates is either primary, due to an enzymatic block in the urea cycle, or secondary, due to organic
acid disorders, fatty acid oxidation defects, congenital sepsis or severe hepatic insufficiency [13].
The plasma level of glutamine and urea cycle intermediates (citrulline and arginine) are helpful
to distinguish between primary and secondary hyperammonemia [1]. The presence of urinary
ketone bodies, hypoglycemia, hyperlactatemia, hypertransaminasemia, elevated serum creatine
phosphokinase and uric acid may help address diagnosis towards metabolic deficits [1]. All of these
biological values were normal in our three patients. Urea cycle disorders were suspected rapidly
because of the respiratory alkalosis, the presence of elevated plasma glutamine level and disturbed
plasma values of urea cycle intermediates.
Our cases manifested typical severe neonatal forms of urea cycle disorders as they presented,
in the very first days of life severe hyperammonemia, encephalopathy and seizures.
Lately, patients’ management for UCDs is becoming more uniform in Europe according to the
literature, mostly on the basis of the recently updated Häberle guidelines [1], which we apply as well.
Pediatr. Rep. 2020, 12 82
Pediatr. Rep. 2020, 12, FOR PEER REVIEW 6

LETHARGY
TACHYPNEA
NEWBORN ASPECIFIC SIGNS
POOR FEEDING
IRRITABILITY

SEPSIS SCREENING and BLOOD GAS

START EMPIRIC
ANTIBIOTHERAPY

ALCALOSIS ACIDOSIS
(Secondary hyperammonemia or
(UCDs)
UCD if late diagnosed)

AMMONIA LEVELS
NH3 between 110 and 200 µmol/L:
NH3 < 110 µmol/L - Prematurity (THAN)
- Sick neonate:
NH3 > 200 µmol/L • Severe perinatal asphyxia
• Liver failure due to multiple causes,
particularily infections
Consider other • Heart failure
diseases
INHERITED METABOLIC DISORDERS

Plasma Glutamine: high Plasma Glutamine: normal

 Secondary hyperammonemia
 UCDs

Figure 2. Diagnostic algorithm for newborns presenting aspecific clinical signs of hyperammonemia.
Figure 2. Diagnostic
NH3: ammonia; UCDs:algorithm for newborns
urea cycle disorders; presenting aspecific
THAN: Transient clinical signs of hyperammonemia.
hyperammonemia of the newborn.
NH3: ammonia; UCDs: urea cycle disorders; THAN: Transient hyperammonemia of the newborn.
The management of UCDs combines dietary and pharmacological therapy. The first line therapy
is to Besides
provide aUCDs, protein-freeothercaloric
causes intake,of better based on intravenous
hyperammonemia should10% be glucose at 10 mg/kg/min
considered as well.
(to prevent endogenous
Hyperammonemia proteiniscatabolism)
in neonates either primary, and dueshouldto anbe enzymatic
started as soon block as in hyperammonemia
the urea cycle, or
is detected. due to organic acid disorders, fatty acid oxidation defects, congenital sepsis or severe
secondary,
hepatic Moreover,
insufficiencyammonia
[13]. The scavengers
plasma level areof the main and
glutamine drugsureauseful to bypass the
cycle intermediates urea cycle,
(citrulline and
thus contributing to reduce plasma ammonia level. All of our
arginine) are helpful to distinguish between primary and secondary hyperammonemia [1]. The patients were treated with sodium
benzoate.ofThe
presence choiceketone
urinary of ammonia
bodies,scavengers
hypoglycemia, varieshyperlactatemia,
by countries: sodium phenylbutyrate is more
hypertransaminasemia, used
elevated
in North
serum America
creatine while sodiumand
phosphokinase benzoate is more
uric acid maycommon throughout
help address Europe
diagnosis [14]. However,
towards metabolic both are
deficits
effective
[1]. All ofchoices,
these and are recommended
biological values werewhen normalplasma ammonia
in our three levels are between
patients. Urea cycle 150 disorders
and 250 µmol/L.
were
Furthermore,
suspected arginine
rapidly becauseand/or of citrulline
the respiratorysupplementation
alkalosis, the could maximize
presence ammonia
of elevated elimination
plasma from
glutamine
the body
level through the
and disturbed urea cycle
plasma values [1].ofAlthough
urea cyclecarnitine is still part of this acute treatment in Europe
intermediates.
(particularly
Our casesinmanifested
Spain), our patients
typical severedidneonatal
not receive forms this molecule
of urea cycle because
disordersitas has been
they proven in
presented, to
have
the little
very benefits
first days ofinlifeUCDssevereandhyperammonemia,
it is, therefore, notencephalopathy
recommended anymore and seizures. by the latest European
guidelines
Lately,[1,14].
patients’ management for UCDs is becoming more uniform in Europe according to the
Continuous
literature, mostly on venovenous
the basis ofhemodiafiltration
the recently updated (CVVHDF)
Häberleshould
guidelinesbe initiated
[1], which urgently
we apply in patients
as well.
unresponsive to dietaryof
The management and pharmacological
UCDs combines dietary treatments, perhaps systematically
and pharmacological therapy.when plasma
The first lineammonia
therapy
levels
is rise above
to provide 500 µmol/L caloric
a protein-free [1]. Despite thebetter
intake, first therapeutic line, increased
based on intravenous 10%plasma ammonia
glucose levels were
at 10 mg/kg/min
stillprevent
(to observed in all our patients,
endogenous proteinwhich led us to
catabolism) andstart CVVHDF.
should As soon
be started as severe
as soon hyperammonemia is
as hyperammonemia is
detected, the patient should be immediately transferred to a center where hemodiafiltration is available.
detected.
Proteins should
Moreover, ammoniabe ideally reintroduced
scavengers are the whenmain ammonia
drugs plasma
useful level falls below
to bypass 100 µmol/L
the urea as in
cycle, thus
cases 2 and 3,toorreduce
contributing at the plasma
latest after
ammonia48 h oflevel.
a protein-free
All of ourcaloric
patientsintake,
were as in case
treated 1, in
with order to
sodium prevent
benzoate.
catabolism,
The choice ofavoid negative
ammonia nitrogenvaries
scavengers balance and prevent
by countries: a rebound
sodium of plasma ammonia
phenylbutyrate is more used levels [1].
in North
America Dietary
while treatment
sodiumfor UCDs varies
benzoate is moresignificantly
common among European
throughout Europe Inherited Metabolic both
[14]. However, Diseases
are
centers. In
effective these patients,
choices, and are it has been recommended
recommended when plasma to administer
ammonia levels the 20–30% (up to 50%
are between 150 inand ARG1
250
deficiency)
µmol/L. of the entire protein
Furthermore, arginineintake and/or as EAA in order
citrulline to maintain growth
supplementation could andmaximize
metabolic control
ammonia [1].
Nevertheless,
elimination in athe
from studybody bythrough
Adam S the et al. including
urea cycle [1].464Although
patients with UCDsisfrom
carnitine several
still part European
of this acute
countries, in
treatment only 30% of(particularly
Europe the cases in in United Kingdom
Spain), received
our patients didthis
notEAA supplementation
receive this molecule becauseand in the rest
it has
of theproven
been Europetothese haverates
littleaverage
benefits38%, in UCDswith and
notable
it is,differences
therefore, notamong countries (100%
recommended anymore in Sweden,
by the
67% in
latest Portugal,guidelines
European 64% in Germany,[1,14]. 38% in Belgium, 29% in Italy and 24% in France) [15]. In the USA,
Continuous venovenous hemodiafiltration (CVVHDF) should be initiated urgently in patients
unresponsive to dietary and pharmacological treatments, perhaps systematically when plasma
ammonia levels rise above 500 µmol/L [1]. Despite the first therapeutic line, increased plasma
Pediatr. Rep. 2020, 12 83

EAA are rather recommended for patients with UCDs [16]. Our three newborns had a protein restricted
diet and received EAA as suggested by the European guidelines [1].
Early diagnosis and management are the key to minimize neurologic sequelae. Hyperammonemia
might generate irreversible injuries to the development of the central nervous system: cortical atrophy,
ventricular enlargement and demyelination leading to cognitive impairment, seizures, mental
retardation and spastic quadriparesis [5,6]. Seizures are present in almost 50% of neonates
diagnosed with hyperammonemia [17] and were observed in all our newborns. The prognosis
and neurodevelopmental outcome should be considered in the therapeutic assessment as well [1].
Neurologic outcome is very poor in presence of intracranial hypertension and/or if plasma ammonia
peaked at above 1000 µmol/L, although the impact of this level on prognosis depends on the duration
of hyperammonemia [1]. The case 1 reached the highest plasma levels with a peak above 1000 µmol/L
during almost 12 h and developed later serious psychomotor development issues. Damages in central
nervous system are reported to be irreversible when peak plasma ammonia levels rise above 480 µmol/L
already [1,5]. Nevertheless, case 3 had a normal psychomotor development at 14 months of age even
though she had the highest initial plasma ammonia level at diagnosis, but of short duration and with
rapid improvement (normalization of ammonemia 12 h after starting treatment). It has been described
that neurologic sequelae depend on the length of the hyperammonemic coma as well: they usually
occur when the exposure to hyperammonemia is longer than two days [18].
In Europe, there is a wide geographic variation in the number of screened metabolic diseases.
In general, even at equal levels of evidence, due to ethical and legal issues and societal implications in
countries with different health systems, decisions on which diseases to include in neonatal screening
programs remain heterogeneous. Italy is the European country where the highest number of inborn
errors of metabolism (IEM) are tested in neonatal screening programs (including, among others,
type 1 and type 2 citrullinemia, argininosuccinic aciduria and hyperargininemia for the UCDs).
In Italy, this number averages 27 IEMs (with more than 40 in Tuscany) compared to 10 IEMs tested in
Belgium [19]. However, some European countries (such as France, Germany, Austria, Switzerland
or Denmark) consider that most pathologies affecting the urea cycle are not eligible for inclusion
in the group of diseases to be screened at birth for several reasons: high number of false positives,
lack of consensus on the individual benefits of early intervention, low number of patients described in
the literature, early onset of symptoms before results of test are known and lack of evidence on the
effectiveness of screening [20]. In our institution, UCDs are not usually screened at birth neither.
Genetic testing are performed in order to confirm diagnosis. Mutation analysis is the method of
choice for definitive diagnosis of UCDs, to help genetic counseling and in some instances to indicate
the prognosis [1].

4. Conclusions
Timely diagnosis of hyperammonemia requires a high index of suspicion. Plasma ammonia should
be measured in all newborns with unexplained symptoms such as poor feeding, irritability, lethargy,
particularly in presence of tachypnea. The presence of respiratory alkalosis is an early sign that will
guide the diagnosis for urea cycle disorders. As delay in treatment may result in progressive neurologic
injury, or even death, a correct diagnosis should be established as soon as possible. The appropriate
conservatory management is critical. The access to the CVVHDF should be anticipated and granted if
unsatisfactory response to first-line therapy.
As UCDs represent an important health problem because of irreversible sequelae if misdiagnosed
and untreated, a single rapid and valid method of screening to help diagnosis might be desirable all
over Europe.

Author Contributions: S.D.R. concepted and designed the work, wrote and structured the manuscript. A.E., A.V.
and C.D.L. gave substantial contributions to conception and design of the manuscript, drafted, structured the
manuscript and revised it critically. O.B., A.-B.J. and J.-P.S. revised the manuscript. All the authors interpreted the
data and managed the patients. All authors have read and approved the submitted manuscript.
Pediatr. Rep. 2020, 12 84

Funding: This study received no funding.

Conflicts of Interest: The authors have no competing interests to declare.
Consent for Publication: An informed consent was obtained by our patients’ parents.

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